KETOTIFEN

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETOTIFEN (KETOTIFEN)

Composition:

Active substance: ketotifen;

1 tablet contains ketotifen (as ketotifen hydrofumarate) – 1 mg (0.001 g);

Excipients: lactose monohydrate, microcrystalline cellulose, magnesium stearate, colloidal anhydrous silicon dioxide, talc.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets.

Pharmacotherapeutic group. Antihistamines for systemic use. Ketotifen. ATC code R06AX17.

Pharmacological Properties.

Pharmacodynamics.

Ketotifen belongs to the group of cycloheptothienones and has a pronounced antihistamine effect. It is a non-bronchodilating antiasthmatic agent. Its mechanism of action is associated with inhibition of histamine and other mediator release from mast cells, blockade of histamine H1-receptors, and inhibition of phosphodiesterase enzyme, resulting in increased levels of cyclic adenosine monophosphate in mast cells. It suppresses the effects of PAF (platelet-activating factor). When used alone, it does not abort asthma attacks but prevents their occurrence and reduces their duration and severity; in some cases, attacks disappear completely.

Pharmacokinetics.

It is almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 2–4 hours. Steady-state levels are achieved after administration of the minimum daily dose of 2 mg. It is approximately 75 % bound to plasma proteins. Volume of distribution is 2.7 L/kg.

Approximately 60 % of the administered dose is metabolized in the liver via three pathways (demethylation, N-oxidation, N-glucuronidation), producing the following metabolites: ketotifen-N-glucuronide (pharmacologically inactive), nor-ketotifen (with pharmacological activity similar to that of unchanged ketotifen), ketotifen N-oxide, and 10-hydroxyketotifen (pharmacological activity unknown).

Elimination is biphasic, with a short half-life of 3 to 5 hours and a longer one of 21 hours. About 1 % is excreted unchanged in urine within 48 hours, and 60–70 % is excreted as metabolites.

Clinical characteristics.

Indications.

Symptomatic treatment of allergic conditions, including allergic rhinitis and conjunctivitis.

Contraindications.

Hypersensitivity to ketotifen or to other components of the medicinal product.

Avoid concomitant use of ketotifen and oral antidiabetic agents (risk of developing reversible thrombocytopenia) until this phenomenon has been sufficiently studied.

Interaction with other medicinal products and other forms of interaction.

When ketotifen and oral antidiabetic agents are used concomitantly, there is a risk of developing reversible thrombocytopenia; therefore, this combination of medicinal products should be avoided.

Concomitant use of ketotifen with atropine and agents with atropine-like effects increases the risk of adverse reactions such as urinary retention, constipation, and dry mouth.

Ketotifen may potentiate the effects of other medicinal products that depress the central nervous system (sedatives, hypnotics).

Concomitant administration of ketotifen with other antihistamines may lead to mutual potentiation of their effects.

Ethanol enhances the CNS-depressant effect of ketotifen.

Special precautions for use.

The drug is ineffective in the treatment of acute allergic reactions and asthma attacks.

The maximum therapeutic effect of the drug occurs after several weeks of regular use.

Normalization of the hypothalamic-pituitary-adrenal system function may take up to 1 year. Therefore, during the first weeks of ketotifen use, previous treatment should be continued and discontinued gradually and over a prolonged period.

At the beginning of long-term ketotifen therapy, other anti-asthmatic drugs, particularly corticosteroids, should not be abruptly discontinued. In patients dependent on steroids, adrenal cortical insufficiency may develop.

In case of intercurrent infection, specific anti-infective therapy should be administered.

Patients must be under medical supervision during treatment due to the possibility of seizures occurring.

Ketotifen should be used with caution in patients with a history of epilepsy, as treatment with the drug may lower the seizure threshold.

Alcohol should not be consumed during ketotifen therapy, as it enhances the drug's depressant effect on the central nervous system.

The drug should be discontinued 10–14 days before performing skin tests for allergy diagnosis.

If ketotifen therapy needs to be discontinued, the dose should be gradually reduced over 2–4 weeks to prevent recurrence of asthma symptoms.

Caution should be exercised when administering ketotifen to patients with impaired liver function.

Since concomitant use with oral hypoglycemic agents may cause thrombocytopenia, such combination should be avoided or platelet levels should be closely monitored if this treatment is indicated.

The drug contains lactose and therefore should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Controlled clinical studies in pregnant women have not been conducted. Although there is no evidence of teratogenic effects, recommendations for the use of the drug during pregnancy cannot be provided.

Ketotifen passes into breast milk; therefore, breastfeeding is not recommended for mothers taking the drug.

Ability to affect reaction speed when driving or operating machinery.

At the beginning of treatment, ketotifen may impair reaction speed; therefore, patients should exercise increased caution when driving or operating automated machinery.

Method of Administration and Dosage

Tablets should be taken orally during meals with water.

Dosing

Adults: 1 tablet (1 mg) twice daily, in the morning and evening, during meals. For patients experiencing a pronounced sedative effect during the first days of treatment, ketotifen should be administered as 1 tablet (1 mg) once daily in the evening only.

If necessary, the daily dose may be increased to 4 mg, i.e., 2 tablets twice daily. When using a higher dose, a more rapid onset of therapeutic effect may be expected.

Children from 6 months to under 3 years of age: ketotifen should be administered in another pharmaceutical form (syrup).

Children aged 3 years and older: 1 tablet (1 mg) twice daily, in the morning and evening, during meals.

Geriatric patients: no special recommendations for elderly patients.

Treatment Duration

Treatment is long-term, and the therapeutic effect is achieved after several weeks of therapy. Treatment should last at least 2–3 months, especially in patients who did not experience symptom improvement during the first weeks.

Concomitant bronchodilator therapy: co-administration of ketotifen with bronchodilators may reduce the frequency of bronchodilator use.

Discontinuation of Therapy

Ketotifen therapy should be discontinued gradually over a period of 2–4 weeks to avoid recurrence of asthmatic symptoms.

Children

Ketotifen is indicated for children aged 3 years and older.

Clinical observations confirm pharmacokinetic characteristics and indicate that children may require a higher dose in mg/kg than adults to achieve optimal results. Higher doses are as well tolerated as lower doses.

Overdose

Symptoms: significant disturbances in psychomotor performance, drowsiness progressing to marked sedation, headache, disorientation, tachycardia, decreased arterial blood pressure; in children – reversible coma, symptoms of central nervous system excitation, including seizures.

Bradycardia, arrhythmia, respiratory center depression, and nystagmus may also occur.

In case of the above-mentioned symptoms, the patient should be thoroughly examined.

Treatment: general measures to remove the non-absorbed portion of the drug from the gastrointestinal tract: induce vomiting, gastric lavage. Administration of activated charcoal may be beneficial. If necessary, symptomatic treatment and monitoring of cardiovascular and respiratory functions are recommended. In cases of agitation, short-acting barbiturates or benzodiazepines may be used.

Adverse reactions

The adverse reactions described below are classified by system organ class and frequency. Adverse reactions are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations:

uncommon – cystitis.

Immune system disorders:

very rare – severe skin reactions, erythema multiforme, Stevens-Johnson syndrome;
frequency not known – skin rashes.

Metabolism and nutrition disorders:

rare – weight gain due to increased appetite.

Psychiatric disorders:

common – psychomotor agitation, irritability, insomnia, restlessness, nervousness;
frequency not known – confusion, somnolence.

Nervous system disorders:

uncommon – dizziness;
rare – sedative effect;
very rare – seizures.

Gastrointestinal disorders:

uncommon – dry mouth;
frequency not known – stomach pain, constipation, nausea, vomiting, dyspeptic disorders.

Hepatobiliary disorders:

very rare – increased liver enzymes, hepatitis.

Renal and urinary disorders:

frequency not known – dysuria.

Dry mouth and dizziness may occur at the beginning of treatment, but usually resolve spontaneously during continued therapy. Symptoms of central nervous system stimulation such as agitation, irritability, insomnia, and anxiety are rarely observed, particularly in children.

Shelf life.

5 years.

Storage conditions.

Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging.

10 tablets per blister; 1 or 3 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address and location of business activity.

36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.